The NF-kappaB inhibitors (bortezomib and DHMEQ) sensitise rituximab-resistant AIDS-B-non-Hodgkin lymphoma to apoptosis by various chemotherapeutic drugs.
Rituximab in combination with chemotherapy is considered for the treatment of patients with AIDS-associated B-cell non-Hodgkin lymphoma (NHL); however, a subgroup of patients does not respond or develops resistance following initial treatments. To address the mechanism of rituximab-resistance, we have generated rituximab-resistant (RR) clones from wild-type (wT) 2F7. A representative 2F7-RR1 clone was examined for its response to rituximab treatment as well as rituximab-mediated chemosensitisation. In comparison with wT-2F7, 2F7-RR1 had less CD20 cell surface expression and failed to respond to rituximab-induced complement-dependent cytotoxicity (CDC) and apoptosis following cross-linking. In addition, rituximab failed to inhibit the constitutively activated p38 MAPK/NF-kappaB pathways and failed to sensitise 2F7-RR1 to various chemotherapeutic drugs (examples: taxol, vincristine, VP16, CDDP). In contrast to rituximab, treatment of 2F7-RR1 with the proteasome inhibitor, bortezomib, and the NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), resulted in inhibition of Bcl-2 expression and sensitisation of 2F7-RR1 to apoptosis by chemotherapeutic drugs. These findings demonstrate that rituximab resistance may be due to failure of rituximab to modify survival pathways. However, pharmacologic inhibitors that inhibit survival pathways can reverse RR tumor cells and sensitise the cells to apoptosis by various chemotherapeutic drugs. These findings offer novel potential therapeutic applications in the reversal of rituximab/drug resistant AIDS-derived B-NHL.
Vega
Mario I
MI
Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, California 90095-1747, USA.
Martinez-Paniagua
Melissa
M
Jazirehi
Ali R
AR
Huerta-Yepez
Sara
S
Umezawa
Kazuo
K
Martinez-Maza
Otoniel
O
Bonavida
Benjamin
B
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D003512:Cyclohexanones / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D016483:Lymphoma, AIDS-Related / Q000188:drug therapy*; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D001549:Benzamides; D001897:Boronic Acids; D003512:Cyclohexanones; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; C464444:dehydroxymethylepoxyquinomicin; D000069283:Rituximab; D000069286:Bortezomib